The humble fruit fly, Drosophila melanogaster, is an important model system, boasting facile genetics, complex organ systems, complex behaviors and a sequenced genome. Fruit flies are easy to propagate and require little lab space. We and our collaborators at NHGRI, NIA, and Incyte Genomics, have been involved in adding high-throughput genomics techniques, such as Expressed Sequence Tags (ESTs) and DNA microarrays to our Drosophila tool-kit and in making reagents for array production widely available to the world-wide Drosophila community. While we have been active in technology, mostly we use fruit flies to address basic biological problems. Our long-term interest has been in determining how the sex of the germ line is established. In other words how a germ line stem cell gives rise to either sperm or eggs. Stem cell development occurs in a defined niche. Our work suggests that when a male stem cell develops in a female niche a tumor results, while when a female stem cell develops in a male environment, stem cell proliferation or survival is poor. We are using microarray technology to identify diagnostic markers for germ line stem cells of the two sexes. We have also expended considerable effort on the detailed analysis of the ovo gene, which is required for the viability of female germ line stem cells regardless of niche environment. The regulatory circuit controlling ovo expression is devilishly complex. The locus encodes both positively and negatively acting transcription factors from alternative promoters. These alternative promoters are cross-regulated by the antagonistic ovo transcription factors. Additionally, the mechanism of ovo biochemical function is unusual, in that ovo proteins bind and function directly at transcription start sites of target genes (locations normally occupied only by basal transcription factors). It will be some time before we fully understand the function and regulation of this fascinating gene. One of the advantages of working on a model organism at the NIH is exposure to scientists interested in a range of topics, from basic research, to insect disease vectors, or translational and clinical studies. We have also participated in the NIH multiple endocrine neoplasia type-1 consortium led by Francis Collins (NHGRI), Steve Marx, and Allen Spiegel (both NIDDK). It is our hope that fruit fly studies will provide a skeletal view of gene regulation pathways to be fleshed out by research on mammalian systems.